3 - lower alkyl or alkoxy - 6 - hydroxy flavans and ester derivatives thereof

ABSTRACT

THE FOLLOWING FLAVANE COMPOUNDS EXHIBIT A CHOLESTEROL-LEVEL-LOWERING ACTIVITY WITHOUT, HOWERE, EFFECTING A NONPHYSIOLOGICAL ACCUMULATION OF DEMOSTEROL OR 7-DEHYDROCHOLESTEROL IN THE STEROLS OF THE SERUM OR OF THE LIVER;   2-(C6H5-),3-R1,6-(R2-O-)CHROMAN   WHEREIN   R1 REPRESENTS ALKYL OR ALKOXY OF 1-6 CARBON ATOMS; R2 REPRESENTS HYDROGEN, ALKYL OF 1-6 CARBON ATOMS, OR AN ESTER, THE ACYL PORTION BEING UP TO 5 CARBON ATOMS.

United States Patent ABSTRACT OF THE DISCLOSURE The following flavane compounds exhibit a cholesterol-level-lowering activity without, however, effecting a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver:

9 Claims wherein R represents alkyl or alkoxy of 1-6 carbon atoms; R represents hydrogen, alkyl of 1-6 carbon atoms, or an ester, the acyl portion being up to carbon atoms.

Applicants hereby claim the benefit of the filing date of West German patent application M 67,001 IVb/12 qu, filed Oct. 20, 1965.

This invention relates to 3,6-disubstituted flavane derivatives.

There are known drugs which can lower the cholesterol level in mammals, for example, 22,25-diaza-cholesterol, triparanol, and dehydro-epiandrosterone-3-diethylamino ethyl ether. Such drugs, however, effect a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver. There is, therefore, a need for agents capable of lowering the cholesterol level in mammals but which do not exhibit the undesired side eifects.

Thus, an object of this invention is to provide cholesterol-level-lowering drugs which do not effect a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver.

Another object is to provide novel and unobvious chemical compounds which are useful as intermediates for the production of further drugs.

An additional object is to provide chemical compounds exhibiting sex hormone activities, particularly female sex hormone activity.

Still another object is to provide pharmaceutical compositions based on the compounds of this invention.

' Further objects include processes for the production of the novel compounds of this invention, as well as the O 14am R20 R! 3,555,047 Patented Jan. 12, 1971 ice wherein R represents alkyl or alkoxy of 1-6 carbon atoms;

R represents hydrogen, alkyl of l-6 carbon atoms, or

R and R" represent methyl, ethyl, or together with the N-atom, pyrrolidino, piperidino, or morpholino; and

n represents 2 or 3,

as well as the esters, the acid addition salts, and the quaternary ammonium derivatives of such compounds. The novel flavane derivatives possess valuable pharmacological properties. They are, therefore, suitable for the preparation of pharmaceutical compositions and are also of value as intermediates for the preparation of further drugs. The novel flavane derivatives particularly exhibit a cholesterol-level-lowering activity, without, however, effecting a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver.

On determination of the blood cholesterol lowering effeet in rats according to the method of Counsell et al. (J. med. pharm. Chem. 5, 720, 1224 [1962] the following percent decreases of the cholesterol level in the serum were found:

Oral

dose, Decrease Compound mg'./kg. percent 2,3-cis-3 methyl-fi-hydroxy-fiavane 25 70 2,3-cis-3ethyl6-hydroXy-flavane 25 40 2,3.cis-3-n-pr0pyl-6-hydroxy-fiavane. 25 39 2,3-eis-3 methoxy-S-hydroxy-flavane. 25 32 2,3-cis-3-ethoxy-G-hydroxy-fiavane 25 23 2,3-cis-3-ethoxy-fi-hydroXy-tlavane 50 40 Furthermore, estrogenic effects are observed. Particularly, estrogenic effects are shown by those 2,3-cis-compounds of Formula I wherein R is lower alkyl (with 1 to 4 carbon atoms) and R is H.

The occurrence of an estrogenic elfect in this class of substances is surprising, since such an activity, in case of nonsteroidal compounds, is generally bound to the structural principle R20-\ II wherein Y represents 3 X is an anion of a strong acid; Z represents H, OH or R and R have the above-indicated meanings; and wherein R 0 can be a phenolic hydroxy group in protected form,

is treated with reducing agents.

(B) 01' a compound of Formula III R107 UII2-\V-CQ1I5 wherein W represents CR =CH or CHR CHX X represents OH or Hail; and

Hal represents Cl, Br, or I;

R and R have the above-indicated meanings; and

wherein R 0 can be a phenolic hydroxy group in protected form,

or a compound of Formula IV X1 IV wherein R R and X have the above-indicated meanings, is

treated with cyclizing agents to split off HX (C) And/or, if desired, in a compound of Formula I, in accordance with conventional methods, an esterified hydroxy group is saponified, or a free hydroxy group is alkylated or acylated by treatment with alkylating or acylating agents.

(D) And/or, if desired, compounds of Formula I are converted, by treatment with acids or alkylating agents, respectively, into the physiologically compatible acid addition salts or quaternary ammonium compounds, respectively.

The wavy line in Formula I means that the residue R, can be in the cis-, as well as in the trans-position with respect to the phenyl group. In the process of this invention, there are obtained either stereoisomeric mixtures which can be separated according to conventional, preferably chromatographic merhods, or there is obtained exclusively, or predominantly, one of the two possible stereoisomers.

Normally, an equilibrium exists between the two isomers; however, upon the addition of an acid, this equilibrium is shifted in favor of the more stable trans-isomer. Conversely, if it is desired, for example, to isolate the cis-isomerproduced primarily in hydrogenation processes involving flavylium salts-the isomerization to the trans-compound can be prevented by adding a base (for example, pyridine) before the working-up process.

Alkyl groups in the residues R and R are, for example: methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, n-amyl, isoamyl, n-hexyl, and isohexyl.

The residue R, can represent, for example, one of the following alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy, tert.butoxy, amyloxy, isoamyloxy, n-hexyloxy, and isohexyloxy, as well as isobutoxy.

Preferred dialkylaminoalkyl groups in the residue R are: Z-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 2-pyrrolidinoethyl, Z-piperidinoethyl, 2-morpholinoethyl, 3-pyrrolidinopropyl, S-piperidinopropyl, and 3-morpholinopropyl.

Esters of such phenolic derivatives (phenols being compounds of Formula I wherein R ==H) are particularly the lower acylates wherein the acyl group contains 1-6 carbon atoms. In detail, typical esters are the formates, acetates, propionates, butyrates, isobutyrates, valerates, isovalerates, trimethylacetates, caproates, isocaproates; furthermore, for example, the nicotinates, isonicotinates, diethylaminoacetates, and the acid addition salts thereof, particularly the hydrochlorides. Especially important are the sulfuric acid and phosphoric acid esters and the physiologically compatible metal salts thereof, particularly the alkali metal salts (for example, sodium) and ammonium salts, since these represent water-soluble derivatives of the compounds of Formula I, which derivatives are thus particularly useful for therapeutic applications.

The expression ester is to include, within the scope of the present invention, the acid addition salts of basic substituted esters and the metal and ammonium salts of acid esters.

The compounds of Formula II comprise flavylium salts, A or A -fiavenes, flavanones, flavanols, or flavones, which can be substituted as stated above. The flavylium salts of Formula II can contain anions of any desired strong acids. The flavylium salts can be present, for example, in the form of the chlorides, bromides, iodides, perchlorates, tetrachloroferrates (III), or hydrogen sulfates.

The reduction of compounds of Formula II is preferably accomplished by catalytic hydrogenation. Suitable catalysts are, for example, noble metal, nickel, and cobalt catalysts, as well as copper chromium oxide. The noble metal catalysts can be used in the form of supported catalysts, such as, for example, palladium on charcoal, calcium carbonate, or strontium carbonate; as oxide catalysts, such as, for example, platinum oxide; or as finely divided metallic catalysts. Nickel and cobalt catalysts are suitably employed as Raney metals; however, nickel is also used in the form of a supported catalyst with kieselguhr or pumice as the support.

The hydrogenation can be conducted at room temperature and normal pressure, or also at elevated temperature and/or elevated pressure. Preferably, the reaction is conducted at pressures between 1 and 100 atmospheres and at temperatures between and +l50 C. Suitably, a solvent is present during this reaction, such as methanol, ethanol, isopropanol, tert.-butanol, ethyl acetate, dioxane, glacial acetic acid, tetrahydrofuran, or water. In some cases, it is advisable to add catalytic amounts of a mineral acid, for example, hydrochloric or sulfuric acid. If a compound of Formula II having a basic nitrogen atom is used for the hydrogenation reaction, it is possible to employ the free base, or also a salt of this base.

During the hydrogenation, care must be taken so that the aromatic rings are not likewise attacked. Therefore, it is preferred to operate under normal pressure in such a manner that the hydrogenation is terminated after the stoichiometric quantity of hydrogen has been absorbed. If starting products of Formula II are employed wherein a phenolic hydroxy group is protected by benzyl, this protective group can be removed during the hydrogenation.

The reduction of the compounds of Formula II can also be conducted successfully with other reducing agents. Thus, flavanones can be converted into fiavanes of Formula I by using diborane; for example, the flavanone is dissolved for this purpose in diethylene glycol dimethyl ether, diborane is introduced under cooling, and the reaction mixture is allowed to stand overnight at room temperature. Furthermore, flavanones can be converted into the thioketals thereof, preferably the ethylene thioketals, which are then split reductively, usually by reaction with Raney metals.

The above-mentioned starting compounds of Formula II can be obtained according to conventional methods. For example, the flavylium salts can be produced by condensing a 2,S-dihydroxybenzaldehyde which is, if desired, etherified or esterified in the 5-position, with a ketone of the formula R CH COC H the A -fiavenes can be prepared by reducing the corresponding flavylium salts with lithium aluminum hydride; the flavanones can be produced by condensation of a 2,5 dihydroxyphenyl alkyl ketone which is, if desired, etherified or esterified in the 5-position, with benzaldehyde. The flavanols are obtainable by reducing the corresponding flavanones, the flavones from the corresponding flavanones by dehydrogenation with selenium dioxide, or by oxidation with hydrogen peroxide in an alkaline solution, and the A -flavenols by reducing the corresponding flavones with lithium aluminum hydride.

Suitable starting compounds of Formula II are, for example, the 3-methyl, 3-ethyl, 3-n-propyl, 3-isopropyl, 3- n-butyl, 3-isobutyl, 3-n-amyl, 3-isoamyl, 3-n-hexyl, 3-isohexyl, 3-methoxy, 3-ethoxy, 3-n-propoxy, 3-isopropoxy, 3- u-butoxy, 3-isobut0xy, B-n-amyloxy, 3-isoamyloxy, 3-nhexyloxy, and 3-isohexyloxy derivatives of 6-hydroxyflavylium chloride, 6 hydroxy 2 fiavene, 6-hydroxy- 3 fiavene, 6 hydroxy fiavanone, 6-hyd-roxy-flavone, 4,6 dihydroxy 2 flavene, and 4,6-dihydroxy-flavane, as well as the 6-esters and 6 ethers thereof, derived from these compounds and corresponding to the meaning of the substituent R The cyclization of compounds of Formula III is normally conducted by the effect of basic or acidic catalysts. Preferably, alkalis are employed in this connection, such as sodium or potassium hydroxide, sodium or potassium amide, sodium hydride, basic-reacting salts, such as sodium or potassium acetate, sodium or potassium carbonate, and organic bases, such as piperidine, pyridine, benzyl trimethylammonium hydroxide. Buffered solutions can also be used, for example those of citric acid and disodium phosphate, or of sodium dihydrogen phosphate and borax, or of boric acid, sodium hydroxide, and potassium chloride. As the preferred acidic catalysts, there are included mineral acids, such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, and polyphosphoric acid; organic sulfonic acids, such as p-toluenesulfonic acid or camphorsulfonic acid; and complexes of organic acids with inorganic acids, such as aluminum chloride, zinc chloride, or tin tetrachloride. These acid catalysts are particularly useful for the cyclization of such compounds of Formula III wherein W represents CR =CH- or CHR CHOH.

The cyclization can be conducted in the presence of an additional inert solvent, such as methanol, ethanol, dioxane, tetrahydrofuran, ethyl acetate, glacial acetic acid, tetralin, benzene, toluene, and, if desired, also in mixtures of these solvents with one another or with water. It is likewise possible to employ an excess of the cyclization agent as the solvent. The cyclization is carried out at room temperature and can be accelerated by heating, preferably to the boiling point of the solvent employed. The reaction time is several minutes to several days.

The starting compounds of Formula III can be produced by condensing a hydroquinone derivative which is, if desired, etherified or esterified with a compound of the formula X -CH WC H It is possible to conduct the reaction in such a manner that the compound of Formula III does not have to be isolated. Furthermore, it is possible to react a compound of the formula OII R20 CH2CHR MgHal whose phenolic hydroxy group(s) can also be present in protected form, with benzaldehyde, in order to obtain the compound of Formula 111; or a chalcone of the formula can be reduced to a compound of Formula III by treatment with a reducing agent, such as sodium amalgam, or

by successive catalytic hydrogenation and reduction with a complex metal hydride.

The preferred starting compounds of Formula III are the following substances:

HO CI-IgClIRr-CHHal-CnI-L as well as the esters and ethers derived from the compounds and corresponding to the substituent R The cyclization of the compounds of Formula IV is conducted generally according to the same methods as the cyclization of the compounds of Formula III. It is not necessary to isolate the compounds of Formula IV which are used as the starting compounds. Rather, these compounds can also be produced in situ. This can be done by reacting a hydroquinone derivative which is, if desired, etherfied or esterified with a halogen compound of the formula X CH -CHR CHHalC H under the conditions set forth above for the cyclization of the compounds of Formula III. When operating under mild alkaline conditions, for example, by treatment with an alkali alcoholate, it is possible to isolate the compounds of Formula IV.

In the above-disclosed reactions of the compounds of Formulae III and IV, it is possible for phenolic hydroxy groups to be present in protected form, inasmuch as the protective groups can be split off under the conditions of condensation. Thus, those compounds wherein hydroxy groups are protected in the form of tetrahydropyranyl ethers can be condensed in an acidic or alkaline medium (in case of an alkaline condensation, the free hydroxy group is liberated from the resultant salt by subsequent brief boiling with acid). Compounds having a hydroxy group protected in the form of an ester can likewise be condensed in an acidic or alkaline medium, the ester group being saponified.

Further suitable protective groups are ether groups, such as benzyl ether or methyl ether. The splitting off of such ethers is conducted, for example, by employing hydrobromic acid as the cyclization agent, under conventional conditions for cleaving phenol ethers.

It is furthermore possible, in a compound of Formula I, to hydrolyze an esterified hydroxy group by treatment With basic or acidic agents. Preferred bases are aqueous, aqueous-alcoholic, or alcoholic sodium or potassium hydroxide. Preferred acids are hydrochloric acid and sulfuric acid.

Conversely, a free hydroxy group can be alkylated or acylated to yield compounds of Formula I. Alkylation can be conducted, for example, by reaction with the corresponding alkyl halogenides, sulfates, or lower alkyl esters in the presence of alkali, such as sodium or potassium hydroxide or carbonate, a conventional inert solvent being optionally present in this reaction. Of particular importance is the formation of a dialkylaminoalkoxy group. Correspondingly, the starting compounds can be reacted with methyl iodide, dimethyl sulfate, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, and isoamyl halogenides, Z-dimethylaminoethyl, 2-diethylaminoethyl, Z-methylethylamino)-ethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 2- morpholinoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, or 3-morpholinopropyl halogenides, or also with the corresponding alcohols. Suitable halogenides are the chlorides, bromides, and iodides. The etherification reactions are conducted, for example, in accordance with the methods of a Williamson synthesis, the starting compounds being the corresponding alkali phenolates. However, it is also possible to react the free phenols with the corresponding alcohols, or substituted amino alcohols, in the presence of acidic catalysts, such as sulfuric acid, phosphoric acid, or ptoluenesulfonic acid.

The hydroxy groups can also be acylated, for example, by heating with an anhydride or halogenide of acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, nicotinic, r isonicotinic acid, preferably in the presence of a base, such as pyridine, or an alkali salt of the corresponding acid, or also a small quantity of a mineral acid, such as sulfuric acid or hydrochloric acid.

For producing the sulfuric acid and phosphoric acid esters of the compounds of Formula I (R =H), these compounds are reacted with sulfuric acid, phosphoric acid, or a derivative of these acids suitable for esterification. The conventional methods known from the literature are employed (see, for example, Houben-Weyl, Methoden der Organischen Che'mie [Methods of Organic Chemistry], vol. VI/2, pp. 452464 [1963], and vol. XII/2, pp. 143-210 [1964], Georg Thieme Publishers, Stuttgart, as well as United States patent application Ser. No. 523,262 (filed Jan. 27, 1966). It is also possible to conduct the reaction with a sulfuric acid or phosphoric acid derivative wherein one or two hydroxy groups of the acid are blocked, and thereafter to remove the protective group from the thus-obtained esters by either hydrolysis or hydrogenolysis. The thus-obtained sulfuric acid or phosphoric acid esters can, in turn, be converted by treatment with bases into the physiologically compatible metal or ammonium salts thereof.

It is also possible to convert basic compounds of Formula I by treatment wtih acids into the physiologically compatible acid addition salts thereof. For this reaction, such acids are suitable which yield physiologically acceptable salts. Thus, organic and inorganic acids can be employed, such as, for example, aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic, monoor polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, d iethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, isonicotinic acid, methane-sulfonic acid, naphthalene-monoand -disulfonic acids, sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or phosphoric acids, such as orthophosphoric acid, etc.

A conversion of basic fiavanes of Formula I into the physiologically compatible quaternary ammonium derivatives thereof is accomplished by treatment with alkylating agents having 18 carbon atoms, such as methyl iodide, dimethyl sulfate, ethyl bromide, and ethyl iodide.

According to this invention, preferred subgeneric groups of compounds are the following, as well as, if desired, the esters, acid addition salts, and quaternary ammonium derivatives thereof:

(a) The compounds of Formula I wherein R, is limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-

amyl, isoamyl, n-hexyl, isohexyl, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, n-amyloxy, isoamyloxy, n-hexyloxy, or isohexyloxy.

(b) The compounds of Formula I wherein R is limited to hydrogen, and R is the same as in (a) above.

(c) The compounds of Formula I wherein R is limited to alkyl of 1-6 carbon atoms.

(d) The compounds of Formula I wherein R is limited to alkoxy of 16 carbon atoms.

(e) The compounds of Formula I wherein R is the same as in (a) above, and R is limited to H or R (CH wherein R is dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino, and n is 2 or 3.

The following compounds are novel and valuable intermediates:

3-methyl-6-hydroxy-fiavylium chloride 3ethyl-6-hydroxy-flavylium chloride 3-n-propyl-6-hydroxy-flavylium chloride 3-n-butyl-6-hydroxy-fiavylium chloride 3-n-amyl-6-hydroxy-flavylium chloride 3-methoxy-6-hydroxy-flavylium chloride 3-ethoxy-6-hydroxy-fiavylium chloride 3-n-propoxy-6-hydroxy-fiavylium chloride 3-n-butoxy-6-hydroxy-flavylium chloride 3-n-amyloxy-6-hydroxy-fiavylium chloride The novel compounds can be employed with conventional pharmaceutical excipients. Carrier substances can be such organic or inorganic compounds suitable for parenteral, enteral, or topical application and which do not react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc. For parenteral application, particularly oily or aqueous solutions, as well as suspensions, emulsions, or implants are employed.

For enteral application, furthermore, suitable are tablets or dragees which are also characterized by the presence of a carbohydrate carrier or binder. A syrup or the like can also be used wherein a sweetened vehicle is employed.

For topical application salves or creams are used which can, if desired, be sterilized or mixed with auxiliary substances, such as preservatives, stabilizers, or wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.

The novel flavane derivatives are preferably administered in dosages of 1-500 mg. per dosage unit. In such pharmaceutical compositions, the carrier is usually present in an amount of 1 to 5,000 mg.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 (a) 10.8 g. 3-methyl-6-hydroxy-fiavylium chloride are catalytic-hydrogenated in 300 ml. methanol in the presence of platinum (produced by the hydrogenation of 1 g. platinum dioxide). After 37 minutes, 1.955 1. hydrogen has been absorbed. The hydrogenation is terminated. The suspension is mixed with 10 ml. pyridine, the platinum is filtered off, and the filtrate is concentrated to dryness under subatmospheric pressure; there is obtained crude 2,3- cis-3-methyl-6-hydroxy-flavane.

Analogously, the following compounds are obtained:

2,3-cis-3-ethyl-6-hydroxy-flavane, 2,3-cis-3-n-propyl-6-hydroxy-fiavane, 2,3-cis-3-methoxy-6-hydroxy-flavane, M.P. 182-185 C.

(from methanol), and 2,3-cis-3-ethoxy-6-hydroxy-fiavane.

2,3-cis-3-ethyl-acetoxy-flavane, 2,3-cis-3-n-propyl-6-acetoxyfiavane, 2,3-cis-3-methoxy-6-acetoxy-flavane, and 2,3-cis-3-ethoxy-6-acetoxy-flavane.

(c) 9.3 g. 2,3-cis-3-methyl-6-acetoxy-flavane are stirred at room temperature in 167 ml. methanolic potassium hydroxide solution for 90 minutes. Cold water, in an amount of 1.7 1., is poured into the reaction mixture, the latter then being acidified with 21 ml. concentrated hydrochloric acid and worked up with chloroform in the usual manner. The thus-obtained 2,3-cis-3-methyl-6- hydroxy-flavane is recrystallized from ether/ hexane, M.P. 130-131" C.

Analogously, there are obtained:

2,3-cis-3-ethyl-6-hydroxy-flavane, M.P. 48-53 C. (from pentane; previously chromatographically purified on silica gel with benzene/ chloroform); 2,3-cis-3-n-propyl-6-hydroxy-flavane, M.P. 78-80" C.

(from ether/pentane); Y 2,3-cis-3-methoxy-6-hydroxy-fiavane, M.-P. 182-185 C.

(from methanol); and 2,3-cis-3-ethoxy-6-hydroxy-flavane, M.P. 146-147 C.

(from ether).

EXAMPLE 2 2 g. 3-methoxy-6-hydroxy-2-fiavene is hydrogenated in ml. ethanol in the presence of 500 mg. Raney nickel.

After the absorption of 1 mol hydrogen, the catalyst is filtered oif, and the solvent is removed under decreased pressure, there being obtained 2,3-cis-3-methoxy-6-hydroxy-flavane, M.P. 182-1 85 C.

EXAMPLE 3 Analogously to Example 2, 1 g. 3-methoxy-6-hydroxy- 3-flavane is hydrogenated to 2,3-cis-3-methoxy-6-hydroxyflavane, M.P. 182-l85 C.

EXAMPLE 4 A solution of 1.5 g. 3-methoxy-6-isoamyloxy-flavanone in 2 ml. ethanedithiol and 2 ml. boron trifluoride etherate is allowed to stand at room temperature for 15 minutes and then, after the addition of 20 ml. chloroform, is allowed to stand overnight. The reaction mixture is diluted with 200 ml. chloroform, washed with water and sodium chloride solution, and dried over sodium sulfate. The residue obtained after the chloroform has been removed is dissolved in 300 ml. absolute ethanol and refluxed with activated Raney nickel for 10 hours. After the catalyst has been filtered olf, the solution is concentrated to 20 ml. Thereby, 2,3-trans-3 methoxy-6-isoamyloxy flavane is obtained.

EXAMPLE 5 2.4 g. 2,3-trans-3-methyl-4,6-dihydroxy-flavane are dissolved in 100 ml. dioxane, mixed with 1.2 g. palladium chloride, and hydrogenated at room temperature. After the stoichiometric quantity of hydrogen has been absorbed, the hydrogenation is terminated, the catalyst is filtered olf, the dioxane solution is concentrated under reduced pressure, diluted with water, and again concentrated for removing the residual dioxane. The crude product is recrystallized from ethanol, there being obtained 2,3- trans-3-methyl-6-hydroxy-flavane.

1 0 EXAMPLE 6 4 g. hydroquinone, 8 g. 1-phenyl-2-methyl-3-bromopropene, and 5 g. freshly melted zinc chloride are boiled under reflux in 55 ml. absolute benzene for 6 hours. Then, the reaction mixture is allowed to cool; the organic phase is washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is chromatograph on 20 g. aluminum oxide, there being obtained 2,3-trans-3-methyl-6-hydroxy flavane.

EXAMPLE 7 2 g. 1 phenyl 2 methyl-3-(2'-hydroxy-5'-methoxyphenyl)-propanol are heated to the boiling point, under reflux, in 10 ml. 2% methanolic hydrochloric acid for 4 hours. Thereafter, the reaction solution is concentrated under reduced pressure, there being obtained 2,3-trans- 3-methyl-6-methoxy-flavane.

EXAMPLE 8 2 g. l-phenyl-2-methyl-3-(2,5'-dimethoxyphenyl)-propanol are boiled under reflux in a 5% solution of hydrogen bromide in 50 ml. glacial acetic acid for 2 hours. Then, the mixture is poured into water, extracted with chloro form, the extract is washed With water, dried over sodium sulfate, and evaporated to dryness, there being obtained 2,3-trans-3-methyl-6-hydroxy-flavane.

EXAMPLE 9 2 g. l-phenyl-2-methyl-3-(2-hydroxy-5'-methoxyphenyl)-propy1 chloride are dissolved cold in 200 ml. 5% solution of caustic soda and subsequently heated on a steam bath. There are obtained 2,3-cisand 2,3-trans-3- methyl-6-methoxy-flavane, which can be separated from each other by chromatographing on silica gel.

EXAMPLE 1O 3 g. 3-phenyl-3-p-anisyloxy-Z-methyl-propyl chloride and 0.3 g. tin tetrachloride are heated in a tubular bomb for 6 hours to 200 C. After cooling, the reaction mixture is Worked up with ether and aqueous hydrochloric acid; the ether phase is washed with soda solution, dried over sodium sulfate, the solvent is Withdrawn under reduced pressure, and the crude product is recrystallized from methanol, there being obtained 2,3-trans-3-methy1-6-methoxyflavane.

EXAMPLE 11 3 g. 3-phenyl-3-p-anisyloxy-2-methyl-propanol are heated with 0.3 g. zinc chloride in a tubular bomb for 30 minutes to 200 C.; after cooling, the reaction mixture is worked up as described in Example 10; 2,3-trans-3-methyl- 6-methoxy-flavane is obtained.

EXAMPLE 12 (a) 5 g. 2,3-cis-3-methoxy-6-hydroxy-flavane and 20 g. 3-dimethylaminopropyl chloride are boiled with 5.7 g. anhydrous potassium carbonate in ml. absolute acetone for 20 hours, under stirring. The reaction mixture is concentrated, water and ether are added, the layers are separated, dried over potassium hydroxide, concentrated by evaporation, and chromatographed on aluminum oxide. With the aid of chloroform, 2,3-cis-3-methoxy-6-(3-dimethylaminopropoxy)-flavane is eluted.

(b) 2 g. 2,3-cis-3-methoxy-6-(3-dimethylaminopropoxy)-flavane are dissolved in a small amount of ethanol and mixed with an excess of ethanolic hydrochloric acid. The precipitated hydrochloride of the base is isolated by filtration.

Analogously, the corresponding hydrobromide can be produced when employing hydrogen bromide.

(c) 0.5 g. 2,3-cis-3-methoxy-6-(3-dimethylaminopropoxy)-flavane is dissolved in ether and mixed with excess methyl iodine. The reaction mixture is allowed to stand for 24 hours at room temperature; then, it is 1 I worked up in the usual manner, and the methiodide of the base is recrystallized from methanol.

((1) 3 g. 2,3-cis-3-methoxy-6-hydroxy-fiavane and 4 g. amidosulfonic acid are introduced, with stirring, into 15 ml. dry pyridine, heated to 90 C. The reaction mixture is maintained at 90 C. for 3 hours. After cooling, 50 ml. absolution ether are added. The ether layer is decanted and the remaining precipitate is mixed with a mixture of 45 ml. 12% solution of caustic soda and 30 ml. dry pyridine, two layers being formed. The pyridine layer is separated, washed twice with a small amount of ether, taken up in methanol, concentrated, and the residue is mixed with ethanol, insoluble components are removed by suction, and the solution is filtered over basic aluminum oxide. From the concentrated filtrate, there crystallizes the sodium salt of 2,3-cis-3-methoxy-6-hydroxyfiavane-6-sulfuric acid ester. After recrystallization from methanol/ethanol, this compound melts at 192-195 C.

EXAMPLE l3 Analogously to Example 1(a), there is obtained by hydrogenation from 3-n-amyl-6-hydroxy-flavylium chloride the compound 2,3-cis-3-n-amyl-6-hydroxy-fiavane, M.P. 102-103 C. (from ether/pentane).

EXAMPLE 14 Aanalogously to Example 1(a), the following compounds are obtained by hydrogenation of the corresponding flavaylium chlorides:

2,3-cis-3-isopropyl-6-hydroxy-flavane 2,3-cis-3 -n-butyl-6-hydroxy-fiavane 2, 3-cis-3-isobutyl-6-hydoxy-fiavane 2,3-cis-3-isoamyl-6-hydroxy-fiavane 2,3-cis-3-n-hexyl-6-hydroxy-flavane 2,3-cis-3-isohexyl-6-hydroxy-flavane 2,3-cis-3 -n-propoxy-6-hydroxy-flavane 2,3-cis-3-isopropoxy-6-hydroxy-fiavane 2,3-cis-3-n-butoxy-6-hydroxy-fiavane 2, 3-cis-3-isobutoxy-6-hydroxy-fiavane 2,3-cis-3-n-amyloxy-fi-hydroxy-flavane 2,3-cis-3-isoamyloxy-6-hydroxy-flavane 2,3-cis-3-n-hexyloxy-6-hydroxy-flavane 2,3-cis-3-isohexyloxy-6-hydroxy-fiavane EXAMPLE 15 (a) Analogously to Example 1(b), the 6-acetates of the 6-hydroxy-flavanes metioned in the preceding examples are obtained.

(b) Analogously to Example 12(d), the 6-sulfuric esters of the 6-hydroxy-flavanes mentioned in the preceding examples and the sodium salts of said sulfuric esters are obtained.

(c) A solution of 2.6 g. 2,3-cis-3-methyl-6-hydroxyflavane in 50 ml. absolute pyridine is added to a solution of 10 ml. phosphorus oxychloride in 100 ml. pyridine at C. and within minutes. After allowing the mixture to stand for hours, it is stirred into a mixture of 1.51. ice and 150 ml. concentrated hydrochloric acid, heated on a steam bath for one hour, cooled, and extracted with ethyl acetate. The extract is washed with 1 N hydrochloric acid and dried over sodium sulfate. After concentrating, the 2,3-cis-3-methyl-6-hydroxy-flavane-6-phosphoric acid ester is obtained. By gently neutralizing the aqueous solution with a sodium carbonate solution and concentrating, the disodium salt is obtained.

Analogously, the 6-phosphoric esters of the 6-hydroxyfiavanes mentioned in the preceding examples and their sodium salts are obtained.

(d) Analogously to Example 12(a) to (c), the

6- (Z-dimethylaminoethyl -ethers, 6- Z-diethylaminoethyl -ethers, 6- (2-pyrrolidinoethyl -ethers,

6- (2-piperidinoethyl) -ethers,

6- 2-morpholinoethyl) -ethers,

1 2 6- 3-dimethylaminopropyl) -ethers, 6-( 3-diethylaminopropyl -ethers, 6- 3-pyrrolidinopropyl -ethers, 6-(3-piperidinopropyl)-ethers, and 6- 3-morpholinopropyl) -ethers of the 6-hydroxy-flavanes mentioned in the preceding examples as well as their hydrochlorides, hydrobromides and methiodides are obtained.

The following examples cover suitable pharmaceutical compositions which can be prepared according to conventional procedures.

EXAMPLE l6TABLETS corn starch and tragacanth. Its weight is about 120 mg.

EXAMPLE 18-SOLUTION FOR INJECTION Ampoules containing 2 mg. 2,3 cis 3 methoxy-6- hydroxy-fiavane in 1 ml. of sesame oil are prepared and sealed in the conventional manner.

EXAMPLE 19SYRUP A mixture of:

2,3-cis-3-methoxy-6-hydroxy-flavane-6-sulfuric Kg.

acid ester sodium salt 0.2 Glycerol (twice distilled) 7.5 Cane sugar 58 Methyl p-hydroxybenzoate 0.07 n-Propyl p-hydroxybenzoate 0.03

Fruit flavorings, as desired.

is dissolved in distilled water in such a manner that the volume of the entire preparation is l.

A dosage unit (5 ml.) contains 10 mg. of active substance.

In place of the substances cited in Examples 16 to 19, it is also possible to incorporate other compounds covered by Formula I as well as the acid addition and quaternary ammonium salts thereof into analogous or similar preparations.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

We claim: 1. A member selected from the group consisting of a 3,6-disubstituted flavane derivative of Formula I /O can mo R1 wherein R represents methyl, ethyl, propyl, amyl, methoxy or ethoxy; R represents hydrogen;

a 6-acetate thereof; a 6-sulfuric acid ester thereof, and a sodium salt of said sulfuric acid ester.

2. A member as defined by claim 1 wherein said member is 2,3-cis-3-methy1-6-hydroxy-flavane.

3. A member as defined by claim 1 wherein member is 2,3-cis-3-ethyl-6-hydroXy-flavane.

4. A member as defined by claim 1 wherein member is 2,3-cis-3-n-pr0pyl-6-hydroxy-flavane.

5. A member as defined by claim 1 wherein member is 2,3-cis-3-n-amyl-6-hydroxy-flavane.

6. A member as defined by claim 1 wherein member is 2,3-cis-3-methoxy-6-hydroxy-flavane.

7. A member as defined by claim 1 wherein member is 2,3-cis-3-ethoxy-6-hydroxy-flavane.

8. A member as defined by claim 1 wherein said member is the sodium salt of 2,3-cis-3-methoXy-6- hydroxy-flavane-6-sulfuric acid ester.

said

said

said

said

said

9. A member as defined by claim 1 wherein said member is a 6-acetate of a compound selected from the UNITED STATES PATENTS 3,433,805 3/1969 Kramer et al. 260--340.5

FOREIGN PATENTS 652,404 1/ 1965 Belgium.

ALEX MAZEL, Primary Examiner I. TOVAR, Assistant Examiner I vs. c1. X.R. 250-2477, 294.7, 325.5; 424-248, 257, 274 

